MX2011007449A - Novel indolyl-oxadiazolyl-diazabicyclononane derivatives and their medical and diagnostical use. - Google Patents

Abstract

This invention relates to novel indolyl-oxadiazolyl-diazabicyclononane derivatives and their use in the manufacture of pharmaceutical compositions. The compounds of the invention are found to be cholinergic ligands at the nicotinic acetylcholine receptors and modulators of the monoamine receptors and transporters. Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.

Description

DERIVATIVES OF INDOLIL-OXADIAZOLIL-DIAZABICICLONONANO AND ITS USE MEDICAL AND DIAGNOSTIC Field of the Invention This invention relates to novel indolyl-oxadiazolyl-diazabicyclononane derivatives and their use in the manufacture of pharmaceutical compositions. The compounds of the invention are found to be cholinergic ligands in nicotinic acetylcholine receptors and modulators of monoamine receptors and transporters.

Due to their pharmacological profile, the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS). , by its acronym in English), diseases or disorders related to smooth muscle contraction, diseases or endocrine disorders, diseases or disorders related to neurodegeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of chemical substance abuse.

Background of the Invention The endogenous cholinergic neurotransmitter, acetylcholine, exerts its biological effect through two types of Ref. : 221675 cholinergic receptors, muscarinic acetylcholine receptors (mAChR) and nicotinic acetylcholine receptors (nAChR).

As it is well established that muscarinic acetylcholine receptors dominate quantitatively on nicotinic acetylcholine receptors in the brain area important for memory and cognition, and much research directed at the development of agents for the treatment of memory-related disorders is has focused on the synthesis of modulators of the muscarinic acetylcholine receptor.

Recently, however, an interest has emerged in the development of nAChR modulators. Several diseases are associated with degeneration of the cholinergic system in this case senile dementia of the Alzheimer's type, vascular dementia and cognitive impairment due to the organic brain damage disease directly related to alcoholism. In fact, several CNS disorders can be attributed to a cholinergic deficiency, a dopaminergic deficiency, an adrenergic deficiency or a serotonergic deficiency.

WO 2004/029053, WO 2007/138037 and O 2007/138038 describe certain oxadiazolyl diazabicyclononane derivatives useful as modulators of monoamine and / or nicotinic receptors. However, derivatives of Oxadiazolyl diazabicyclononane of the present invention have never been described.

Summary of the Invention The present invention is dedicated to the provision of novel modulators of monoamine and / or 'nicotinic receptors, modulators are useful for the treatment of diseases or disorders related to cholinergic receptors, and in particular the nicotinic acetylcholine receptor (nAChR). ), the serotonin receptor (5-HTR), receptor. dopamine (DAR) and the norepinephrine receptor (NER), and the biogenic amine transporters for serotonin (5-HT), dopamine (DA) and norepinephrine (NE).

Due to its pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS), diseases or disorders related to contraction of smooth muscle, diseases or endocrine disorders, diseases or disorders related to neurodegeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of chemical substance abuse.

The compounds of the invention may also be useful as diagnostic tools or monitoring agents in various diagnostic methods, and in particular for in vivo receptor imaging (neuroimaging), and can be used in marked or unmarked form.

In its first aspect the invention provides novel indolyl-oxadiazolyl-diazabicyclononane derivatives represented by Formula I a stereoisomer thereof or a mixture of its stereoisomers, in labeled or unlabeled form, or a pharmaceutically acceptable salt thereof, wherein Ar 'represents an indolyl group selected from lH-indol-4-yl, lH-indole-5- ilo, lH-indol-6-yl and lH-indol-7-yl, whose indolyl group is optionally N-substituted with alkyl, alkenyl, alkynyl, haloalkyl or cycloalkyl; and / or C-substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, and amino.

In its second aspect the invention provides pharmaceutical compositions comprising a therapeutically effective amount of the indolyl-oxadiazolyl-diazabicyclononane derivatives of the invention, a stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt. acceptable thereof, together with at least one pharmaceutically acceptable carrier or diluent.

In a third aspect the invention relates to the use of the indolyl-oxadiazolyl-diazabicyclononane derivatives of the invention, a stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, for the manufacture of a composition / pharmaceutical medicament for the treatment, prevention or alleviation of a disease or disorder or condition of a mammal, including a human being, whose disease, disorder or condition is responsive to the modulation of cholinergic receptors and / or receptors of monoamine In a fourth aspect the invention provides pharmaceutical compositions comprising a diagnostically effective amount of a labeled indolyl-oxadiazolyl-diazabicyclononane derivative of the invention, or a pharmaceutically acceptable addition salt thereof, together with at least one pharmaceutically acceptable carrier or diluent. .

In a fifth aspect the invention provides methods of treatment, prevention or alleviation of diseases, disorders or conditions of a living animal body, including a human being, whose disorder, disease or condition is responsive to the modulation of cholinergic receptors and / or receptors of monoamine, the method comprises the step of administering to a living animal body in need thereof a therapeutically effective amount of the indolyl-oxadiazolyl-diazabicyclononane derivatives of the invention.

In a final aspect the invention provides methods for the non-invasive determination of the distribution of a tracer compound within an intact, whole human or animal body using a physical detection method, wherein the tracer compound is a compound of the formula ( I) according to the invention, or any of its enantiomers or any mixture thereof, or a pharmaceutically acceptable salt thereof, in marked form.

Other objects of the invention will be apparent to the person skilled in the art from the description and the following detailed examples.

Detailed description of the invention Indolyl-oxadiazolyl-diazabicyclononane derivatives In a first aspect the invention provides novel indolyl-oxadiazolyl-diazabicyclononane derivatives represented by Formula I a stereoisomer thereof or a mixture of its stereoisomers, in marked or unlabelled form, or a salt pharmaceutically acceptable thereof, wherein Ar 'represents an indolyl group selected from lH-indol-4-yl, lH-indol-5-yl, lH-indol-6-yl and lH-indol-7-yl, whose group indolyl is optionally N-substituted with alkyl, alkenyl, alkynyl, haloalkyl or cycloalkyl; and / or C-substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, and amino.

In a preferred embodiment the indolyl-oxadiazolyl-diazabicyclononane derivative of the invention is a compound of formula I, a stereoisomer thereof or a mixture of its stereoisomers, in a labeled or unlabelled form, or a pharmaceutically acceptable salt thereof, wherein Ar 'represents an indolyl group selected from lH-indol-4-yl, lH-indol-5-yl, 1H-indol-6-yl and 1H-indol-7-yl, whose indolyl group is optionally N-substituted with alkyl, alkenyl, alkynyl, haloalkyl or cycloalkyl. In a preferred embodiment Ar 'represents an indolyl group selected from lH-indol-4-yl, lH-indol-5-yl, lH-indol-6-yl and lH-indol-7-yl.

In another more preferred embodiment, Ar 'represents lH-indol-4-yl, of which the indolyl group is optionally N-substituted with alkyl, alkenyl, alkynyl, haloalkyl or cycloalkyl.

In a third preferred embodiment Ar 'represents 1H-indol-4-yl.

In a fourth preferred embodiment Ar 'represents 1H-indol-5-yl, which indolyl group is optionally N-substituted with alkyl, alkenyl, alkynyl, haloalkyl or cycloalkyl.

In a fifth, more preferred embodiment, Ar represents 1H-indol-5-yl.

In a sixth preferred embodiment Ar 'represents 1H-indol-6-yl, whose indolyl group is optionally N-substituted with alkyl, alkenyl, alkynyl, haloalkyl or cycloalkyl.

In a seventh most preferred embodiment Ar 'represents lH-indol-6-yl, whose indolyl group is optionally N-substituted with alkyl or haloalkyl.

In an eighth most preferred embodiment Ar 'represents 1H-indol-6-yl, the indolyl group of which is optionally N-substituted with alkyl, and in particular methyl, ethyl or isopropyl.

In a ninth most preferred embodiment Ar 'represents 1H-indol-6-yl, which indolyl group is optionally N-substituted with haloalkyl, and in particular 2-fluoroethyl.

In a tenth most preferred embodiment Ar 'represents 1H-indol-6-yl.

In a most preferred eleventh embodiment Ar 'represents lH-indol-7-yl, which indolyl group is optionally N-substituted with alkyl, alkenyl, alkynyl, haloalkyl or cycloalkyl.

In a twelfth most preferred embodiment Ar 'represents lH-indol-7-yl.

In still a more preferred embodiment the indolyl-oxadiazolyl-diazabicyclononane derivative of the invention is 4- [5- (l-Methyl-lH-indol-6-yl) - [1,3,4] oxadiazol-2-yl] -1,4-diaza-bicyclo [3.2.2] nonane; 4- . { 5- [1- (2-Fluoro-ethyl) -lH-indol-6-yl] - [1,3, 4] oxadiazole -2-yl} -l, 4-diaza-bicyclo [3.2.2] nonane; 2- (1, 4 -diazabicyclo [3.2.2] nonan-4-yl) -5- (lH-indol-6-yl) -1,3,4-oxadiazole; 2- (1, 4 -diazabicyclo [3.2.2] nonan-4 -i1) -5- (1-isopropylindol-6-yl) -1,3,4-oxadiazole; or 2- (1, 4 -diazabicyclo [3.2.2] nonan-4-yl) -5- (1-ethylindol-6-yl) -1,3,4-oxadiazole; a stereoisomer thereof or a mixture of its stereoisomers, in marked or unlabelled form, or a pharmaceutically acceptable salt thereof. In still another preferred embodiment the indolyl-oxadiazolyl-diazabicyclononane derivative of the invention is 4 - . 4 - . { 5 - [1- (2- [18F] -Fluoro-ethyl) -lH-indol-6-yl] - [1,3,4] oxadiazol-2-yl} -1, 4 -diaza-bicyclo [3.2.2] nonane; a stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof.

Any combination of two or more of the embodiments described herein is considered within the scope of the present invention.

Definition of substituents In the context of this invention halo represents fluoro, chloro, bromo or iodo.

In the context of this invention a haloalkyl group denotes an alkyl group as defined herein, the alkyl group is substituted one or more times with halo. Preferred haloalkyl groups of the invention include mono, di- or trihalomethyl, preferably trifluoromethyl. Other preferred haloalkyl groups of the invention include mono, di- or trifluoryl ethyl, preferably 2-fluoro-ethyl.

In the context of this invention, an alkyl group denotes a univalent saturated or linear branched hydrocarbon chain. The hydrocarbon chain preferably contains from one to eighteen carbon atoms (alkyl-Ci-is), more preferred from one to six carbon atoms (Ci-6-alkyl); lower alkyl), including pentyl, isopentyl, neopentyl, hexyl and isohexyl. In a preferred embodiment alkyl represents a C1-alkyl group, including butyl, isobutyl, secondary butyl and tertiary butyl. In another preferred embodiment of this invention alkyl represents an alkyl-Ci-3 group, which may be particularly methyl, ethyl, propyl or isopropyl.

In the context of this invention, an alkenyl group denotes a straight or branched carbon chain containing one or more double bonds, including di-ions, tri-ions and poly-ions. In a preferred embodiment the alkenyl group of the invention comprises from two to eight carbon atoms (C2-8 alkenyl) / more preferred from two to six carbon atoms (C1-6 alkenyl), including at least one double bond . In a preferred embodiment, the alkenyl group of the invention is ethenyl; 1- or 2-propenyl (allyl); 1-, 2- or 3-butenyl, or 1,3-butadienyl; 1-, 2-, 3-, 4-, or 5-hexenyl, or 1,3-hexadienyl, or 1, 3, 5-hexatrienyl; 1-, 2-, 3-, 4-, 5-, 6-, or 7-octenyl, or 1,3-octadienyl, or 1, 3, 5-octanethienyl, or 1,3,5,7-octatetraenyl.

In the context of this invention, an alkynyl group denotes a linear or branched carbon chain containing one or more triple bonds, including di-ions, tri-ions and poly-ions. In a preferred embodiment the alkynyl group of the invention comprises from two to eight carbon atoms (C2-8 alkynyl) more preferred from two to six carbon atoms (C2-6 alkynyl) / including at least one triple bond. In its most preferred embodiment, the alkynyl group of the invention is ethynyl; 1-, or 2 -propynyl; 1-, 2-, or 3-butynyl, or 1,3-butadiinyl; 1-, 2-, 3-, 4-pentynyl, or 1,3-pentadiinyl; 1-, 2-, 3-, 4-, or 5-hexynyl, or 1,3-hexadinyl or 1, 3, 5-hexatriinyl; 1-, 2-, 3-, 4-, 5- or 6-heptinyl, or 1,3- Heptidinyl, or 1, 3, 5-heptytrinyl; 1-, 2-, 3-, 4-, 5-, 6- or 7-octynyl, or 1,3-octyndiinyl, or 1, 3, 5-octtriinyl, or 1,3,5,7-octtethryl.

In the context of this invention a cycloalkyl group denotes a cyclic alkyl group, preferably containing from three to seven carbon atoms (C3-7 cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In the context of this invention the alkoxy group denotes an "alkyl-O" group, wherein the alkyl is as defined above. Examples of preferred alkoxy groups of the invention include methoxy, ethoxy and isopropoxy.

Estheric isomers It will be appreciated by persons skilled in the art that the compounds of the present invention can exist in different stereoisomeric forms, including enantiomers, diastereomers, as well as geometric isomers (cis-trans isomers). The invention includes all stereoisomers and any mixture thereof including racemic mixtures.

The racemic forms can be resolved within the optical antipodes by known methods and techniques. One way to separate the enantiomeric compounds (including enantiomeric intermediates) is - in the case that the compound is a chiral acid - by the use of an amine optically active, and releasing the resolved diastereomeric salt, by treatment with an acid. Another method for resolving racemates within the optical antipodes is based on chromatography in an optical active matrix. The racemic compounds of the present invention can thus be resolved in their optical antipodes, for example, by fractional crystallization of D- or L- salts (tartrates, mandelates, or camphorsulfonate) for example.

Additional methods for the resolution of optical isomers are known in the prior art. Such methods include those described by Jaques J, collet A, & Wilen S in "Enantiomers, Racemates, and Resolutions", John iley and Sons, New York (1981).

The optical active compounds can also be prepared from optically active starting materials or intermediates.

Pharmaceutically acceptable salts The indolyl-oxadiazolyl-diazabicyclononane derivative of the invention can be provided in any form suitable for the intended administration. Appropriate forms include pharmaceutically acceptable salts (in this case physiologically), and pre- or prodrug forms of the compound of the invention.

Examples of pharmaceutically acceptable addition salts include, without limitation, the addition salts of non-toxic inorganic and organic acid such as hydrochloride derived from hydrochloric acid, hydrobromide derived from hydrobromic acid, nitrate derived from nitric acid, perchlorate derived from perchloric acid, phosphate derived from phosphoric acid, sulphate derived from sulfuric acid, the format derived from formic acid, acetate derived from acetic acid, acononate derived from aconitic acid, ascorbate derived from ascorbic acid, benzenesulfonate derived from benzenesulfonic acid, benzoate derived from benzoic acid, cinnamate derived from cinnamic acid, citrate derived from citric acid, embonate derived from embonic acid, enanthate derived from enanthic acid, fumarate derived from fumaric acid, glutamate derived from glutamic acid, glycollate derived from glycolic acid, lactate derived from lactic acid, maleate derived from maleic acid, the malonate derives of malonic acid, mandelate derived from mandelic acid, methanesulfonate derived from methane sulphonic acid, naphthalene-2-sulfonate derived from naphthalene-2-sulfonic acid, phthalate derived from italic acid, salicylate derived from salicylic acid, sorbate derived from sorbic acid, stearate derived from stearic acid, succinate derived from succinic acid, tartrate derived from tartaric acid, toluene-p-sulfonate derived from p-toluene sulfonic acid, and the like. Such Salts can be formed by methods well known and described in the prior art.

Other acids such as oxalic acid, which can not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a compound of the invention and its pharmaceutically acceptable acid addition salt.

Examples of pharmaceutically acceptable cationic salts of a compound of the invention include, but are not limited to, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline, lysine, and salt thereof. ammonium, and the like, of a compound of the invention containing an anionic group. Such cationic salts can be formed by sufficiently known processes and described in the prior art.

Additional examples of the pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride, the hydrobromide, the nitrate, the perchlorate, the phosphate, the sulfate, the format, the acetate , the aconate, the ascorbate, the benzenesulfonate, the benzoate, the cinnamate, the citrate, the embonate, the enanthate, the fumarate, the glutamate, the glycolate, the lactate, the maleate, the malonate, the mandelate, the methanesulfonate, the Naphthalene-2-sulfonate derivative, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulfonate, and the like. Such salts can be formed by well known processes and described in the prior art.

The metal salts of an indolyl-oxadiazolyl-diazabicyclononane derivative of the invention include alkali metal salts, such as the sodium salt of a compound of the invention which contains a carboxy group.

In the context of this invention the "onium salts" of the N-containing compounds are also contemplated as pharmaceutically acceptable salts. Preferred "onium salts" include the alkyl-onium salts, the cycloalkyl-onium salts, and the cycloalkylalkyl-aluminum salts.

Marked Compounds The compounds of the invention can be used in their labeled or unlabelled form. In the context of this invention the labeled compound has one or more atoms substituted by an atom having an atomic mass or a mass number different from the atomic mass or mass number usually found in nature. The labeled compound according to the invention preferably contains at least one radionuclide as a label, also known as radioactive isotopes or radioisotopes. The marking will allow easy quantitative detection of the compound.

The labeled compounds of the invention may be useful as diagnostic tools, radiotracers, or monitoring agents in various diagnostic methods, and for imaging the receptor in vivo.

Radionuclides that emit positrons are all candidates for use. In the context, of this invention the radionuclide is preferably selected from 2H (deuterium), 3 H (tritium), "c, 13 C, 14 C, 131 I, 1251, 123 I, and 18 F. In a preferred embodiment the radionuclide is 18 F.

The physical method for detecting the labeled isomer of the present invention can be selected from Positron Emission Tomography (PET), Computed Tomography by Individual Photon Emission (SPECT), Spectroscopy of Magnetic Resonance Imaging (MRS), Magnetic Resonance Imaging (MRI), Computed Axial X-ray Tomography (CAT), Computed tomography (CT), Functional Magnetic Resonance Imaging (fMRI) and combinations thereof. In a preferred embodiment, the detection method is Positron Emission Tomography (PET scan).

Neuroimaging The compounds of the invention, particularly those which are selective for the nicotinic subtype OI7 receptor, may be useful as diagnostic tools, radiotracers or monitoring agents in various diagnostic methods, and in particular for projecting the receptor image in vivo (neuroimaging ).

In another aspect of the invention, a method for the non-invasive determination of the distribution of a tracer compound within an intact, whole living human or animal body using a physical detection method. According to this method a tracer compound is a compound of the invention, or any of its enantiomers or any mixture thereof, or a pharmaceutically acceptable salt thereof, in marked or unlabelled form.

In a preferred embodiment the physical detection method is selected from PET, SPECT; MRS, MRI, CAT, or combinations thereof.

The labeled compound of the invention preferably contains at least one radionuclide as a label. Radionuclides that emit positrons are all candidates for use. In the context of this invention the radionuclide is preferably selected from 2H (deuterium), 3H (tritium), "C, 13C, 14C, 150, 13N, 123I, 125I, 131I, 18F and 99raTc In a preferred embodiment the radionuclide is 18F.

Examples of commercially available labeling agents that can be used in the preparation of the labeled compounds of the present invention are [1: LC] 02, 18F, and Nal with different iodine isotopes. In particular [1: LC] 02 can be converted to a methylation agent- [1XC], such as [^ CjHal or methyl triflate- ["c].

The tracer compound can be selected according to with the chosen detection method.

In a preferred embodiment, the labeled or unlabeled compound of the invention can be detected by an appropriate spectroscopic method, in particular UV spectroscopy and / or fluorescence spectroscopy.

In another preferred embodiment, the compounds of the invention marked by the incorporation of an isotope in the molecule, which can be in particular an isotope of the natural atoms including 2H (deuterium), 3H (tritium), 1: LC, 13C, 14C , 150, 13N, 1 3I, 125I, 131I, 18F and 99mTc, and the incorporation of the isotope can be measured by conventional scintillation counting techniques.

The labeled compounds containing for example alkyl [18F] labeled as a substituent on the ring N atom in the indole group can be prepared according to what is described for example Deuther-Conrad et al. [innie Deuther-Conrad, Steffen Fischer, Achim Hiiler, Elsebet 0stergaard Nielsen, Daniel Brunicardi Timmermann, Jorg Steinbach, Osama Sabri, Dan Peters, Peter Brust: Molecular imaging of o7 nicotinic acetylcholine receptors: design and evaluation of the potent radioligand [ 18F] NS10743; Eur J Nucí Med Mol Imaging published online on January 10, 2009.

In a third preferred embodiment, the physical method for detecting the tracer compound of the present invention is selected from Positron Emission Tomography.

(PET), Computed Tomography by Emission of Individual Photons (SPECT), Magnetic Resonance Spectroscopy (MRS), Magnetic Resonance Imaging (MRI), Computed Axial X-ray Tomography (CAT) or combinations of them. In a preferred embodiment, the physical method for detecting the tracer compound of the present invention is Positron Emission Tomography (PET).

In a preferred additional embodiment the invention provides a method for the non-invasive determination of the distribution of a tracer compound within an intact, intact human or animal body using a physical detection method, wherein the tracer compound is a compound of the invention. invention, or any of its enantiomers or any mixture thereof, or a pharmaceutically acceptable salt thereof, in labeled form.

In a more preferred embodiment the compound for use according to the invention is marked by the incorporation of 18F, and the incorporation of the isotope is measured by the Positron Emission Tomography (PET) or Individual Photon Emission Computed Tomography (SPECT). .

In an even more preferred embodiment, the compound for use according to the invention is 4-. { 5- [1- (2- [18F] -Fluoro-ethyl) -lH-indol-6-yl] - [1,3,4] -oxadiazol-2-yl} - 1, 4 -diaza-bicyclo [3.2.2] nonane, a stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically salt acceptable of them.

Prior to performing the method of the present invention, a diagnostically effective amount of a labeled or unlabeled compound of the invention is administered to a living body, including a human.

The diagnostically effective amount of the labeled or unlabeled compound of the invention that will be administered prior to conducting the in vivo method for the present invention is within a range of from 0.1 ng to 100 mg per kg of body weight, preferably within a range of 1 mg to 10 ng per kg of body weight.

Methods of producing indolyl-oxadiazolyl-diazabicyclononane derivatives The indolyl-oxadiazolyl-diazabicyclononane derivative of the invention can be prepared by conventional methods for chemical synthesis, for example those described in the working examples. The starting materials for the processes described in the present application are known or can be easily prepared by conventional methods of commercially available chemicals.

Also a compound of the invention can be converted to another compound of the invention using conventional methods.

The final products of the reactions described here can be isolated with conventional techniques, for example by extraction, crystallization, distillation, chromatography, etc.

Biological Activity The compounds of the invention are found to be cholinergic ligands in nicotinic acetylcholine receptors and modulators of monoamine receptors and transporters. In a preferred embodiment the invention is dedicated to the provision of novel ligands and modulators of nicotinic receptors, which ligands and modulators are useful for the treatment of diseases or disorders related to cholinergic receptors, and in particular the nicotinic acetylcholine receptor ( nAChR). Preferred compounds of the invention show a nicotinic receptor selectivity of pronounced acetylcholine subtype O.sub.7.

Due to its pharmacological profile the compounds of the invention can be useful for the treatment of diseases or conditions as diverse as diseases related to the CNS, diseases related to PNS, diseases related to. smooth muscle contraction, endocrine disorders, diseases related to neurodegeneration, diseases related to inflammation, pain, and withdrawal symptoms caused by the termination of chemical abuse.

In a preferred embodiment the compounds of the present invention can be useful for the treatment, prevention or relief of a cognitive disorder, learning deficit, deficit and memory dysfunction, Down syndrome, Alzheimer's disease, attention deficit, attention deficit with hyperactivity disorder (ADHD), Tourette syndrome, psychosis, depression, bipolar disorder, mania, manic depression, schizophrenia, cognitive or attention deficits related to schizophrenia, obsessive compulsive disorders (OCD), panic disorders, eating disorders such as anorexia nervosa, bulimia and obesity, narcolepsy, nociception, AIDS dementia, senile dementia, autism, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, anxiety, anxiety disorders without OCD, seizure disorders, epilepsy, neurodegenerative disorders, transient anoxia, induced neurodegeneration, neuropathy, diabetic neuropathy, peripheral dyslexia, tardive dyskinesia / hyperkinesia, mild pain, moderate or severe pain, acute, chronic or recurrent pain, pain caused by migraine, postoperative pain, phantom limb pain, inflammatory pain, neuropathic pain, chronic headache, central pain, pain related to diabetic neuropathy, postherpetic neuralgia, or peripheral nerve injury, bulimia, post-traumatic syndrome, social phobia, sleep disorders, pseudodementia, Ganser syndrome, pre-menstrual syndrome, late luteal phase syndrome, ibromyalgia, chronic fatigue syndrome, mutism, trichotillomania, time decompensation, arrhythmias, smooth muscle contractions, angina pectoris, premature labor, diarrhea, asthma, tardive dyskinesia, hyperkinesia, premature ejaculation , erectile difficulty, hypertension, inflammatory disorders, inflammatory skin disorders, acne, rosacea, Crohn's disease, inflammatory bowel disease, ulcerative colitis, diarrhea, or withdrawal symptoms caused by the termination of use of addictive substances, including products that they contain nicotine such as tobacco, opioids such as heroin, cocaine and morphine, benzodiazepines and drugs similar to benzodiazepine, and alcohol.

In a more preferred embodiment the compounds of the invention may be useful for the treatment, prevention or alleviation of pain, mild or moderate or severe pain, acute, chronic or recurrent pain, pain caused by migraine, postoperative pain, limb pain. phantom, inflammatory pain, neuropathic pain, chronic headache, central pain, pain related to diabetic neuropathy, postherpetic neuralgia, or peripheral nerve injury.

In an even more preferred embodiment the compounds of the invention may be useful for the treatment, prevention or relief of diseases, disorders or conditions associated with smooth muscle contractions, seizure disorders, angina pectoris, premature labor, seizures, diarrhea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, premature ejaculation, or erectile difficulty.

In yet an even more preferred embodiment, the compounds of the invention may be useful for the treatment, prevention or alleviation of a neurodegenerative disorder, transient anoxia, or induced neurodegeneration.

In yet a more preferred embodiment the compounds of the invention may be useful for the treatment, prevention or alleviation of an inflammatory disorder, inflammatory skin disorder, acne, rosacea, Crohn's disease, inflammatory bowel disease, ulcerative colitis, or diarrhea.

In a further preferred embodiment the compounds of the invention may be useful for the treatment, prevention or alleviation of diabetic neuropathy, schizophrenia, cognitive or attention deficits related to schizophrenia, or depression.

Finally, the compounds of the invention may be useful for the treatment of withdrawal symptoms caused by the termination of the use of addictive substances. Such addictive substances include nicotine containing products such as tobacco, opioids such as heroin, cocaine and morphine, benzodiazepines, benzodiazepine-like drugs, and alcohol. The withdrawal of addictive substances is in general a traumatic experience characterized by anxiety and frustration, anger, anxiety, difficulties in concentration, insomnia, decreased heart rate and increased appetite and weight gain.

In this context "treatment" includes treatment, prevention, prophylaxis and relief of withdrawal and withdrawal symptoms as well as treatment that results in decreased voluntary consumption of the addictive substance.

In another aspect, the compounds of the invention are used as diagnostic agents, for example for the identification and localization of nicotinic receptors in various tissues.

It is now contemplated that an appropriate dosage of the active pharmaceutical ingredient (API) is in the range of from about 0.1 to about 1000 API per day, more preferred from about 10 to about 500 API mg per day, most preferred from about 30 to about 100. mg API per day, dependent, however, on the exact mode of administration, the form in which it is administered, the indication considered, the subject and in particular the body weight of the subject involved, and also the preference and experience of the doctor or veterinarian responsable.

The preferred compounds of the invention show a biological activity in the sub-micromolar and micromolar range, in this case from below from 1 to approximately 100 μ ?.

Pharmaceutical Compositions In another aspect the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the compound of the invention.

While an indolyl-oxadiazolyl-diazabicyclononane derivative of the invention for use in therapy can be administered in the form of unprocessed compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, into a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffer solutions, diluents, and / or other customary pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceutical compositions comprising the indolyl-oxadiazolyl-diazabicyclononane derivative of the invention, or a pharmaceutically acceptable salt or a derivative thereof, together with one or more pharmaceutically acceptable carriers, and, optionally, other ingredients therapeutic and / or prophylactic, known and used in the prior art. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

The pharmaceutical composition of the invention can be administered by any convenient route, which satisfies the desired therapy. Preferred routes of administration include oral administration, in particular in tablet, capsule, dragee, powder, or liquid form, and parenteral administration, in particular cutaneous, subcutaneous, intramuscular, or intravenous injection. The pharmaceutical composition of the invention can be manufactured by any person skilled in the art by means of standard methods and conventional techniques appropriate for the desired formulation. When desired, compositions adapted to give sustained release of the active ingredient can be employed.

The pharmaceutical compositions of the invention may be those suitable for oral, rectal, bronchial, nasal, pulmonary, topical (including buccal and sublingual) administration transdermal, vaginal or parenteral (including injection or cutaneous infusion, subcutaneous, intramuscular, intraperitoneal, intravenous, intrarterial, intracerebral, intraocular), or those in a form suitable for administration by inhalation or insufflation, including powders and liquid administration in aerosol, or by sustained release systems. Appropriate examples of sustained release systems include matrices semipermeable of solid hydrophobic polymers containing the compound of the invention, the matrices may be in the form of formed articles, for example films or microcapsules.

The indolyl-oxadiazolyl-diazabicyclononane derivative of the invention, together with a conventional adjuvant, carrier, or diluent,. thus it can be placed in the form of pharmaceutical compositions and appropriate unit dosages. Such forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled therewith, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any appropriate effective amount of the active ingredient commensurate with the daily dosage range. expected to be employed.

The indolyl-oxadiazolyl-diazabicyclononane derivative of the present invention can be administered in a wide variety of oral and parenteral dosage forms. Be It is obvious to a person skilled in the art that the following dosage forms may comprise, as the active component, a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.

To prepare the pharmaceutical compositions of an indolyl-oxadiazolyl-diazabicyclononane derivative of the present invention, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, seals, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component.

In tablets, the active component is mixed with the carrier having the necessary binding capacity in appropriate proportions and compacted in the desired shape and size.

The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. The appropriate carriers are carbonate magnesium, magnesium stearate, talc, sugar, lactose, pectin, dextrin, cellulose, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting point wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with the encapsulating material as a carrier that provides a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with the. Similarly, stamps and dragees are included. Tablets, powders, capsules, pills, seals, and lozenges can be used as solid forms suitable for oral administration.

To prepare suppositories, a low melting point wax, such as a mixture of fatty acid glyceride or cocoa butter, first melts and the active component is dispersed homogeneously therein, by agitation. The molten homogeneous mixture is then poured into molds of appropriate size, allowed to cool, and thus solidify.

Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or aerosols containing in addition to the active ingredient such carriers as are known in the prior art to be appropriate.

Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, liquid parenteral injection preparations can be formulated as solutions in aqueous polyethylene glycol solution.

The indolyl-oxadiazolyl-diazabicyclononane derivative according to the present invention can thus be formulated for parenteral administration (for example by injection, for example bolus injection or continuous infusion) and can be presented as a unit dose in ampoules, prefilled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization of the solution, for constitution with an appropriate vehicle, for example sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as wanted .

Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

Solid form preparations, intended for conversion shortly before being used for liquid form preparations for oral administration, are also included. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active component such preparations may comprise coloring agents, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

For topical administration to the epidermis the indolyl-oxadiazolyl-diazabicyclononane derivative of the invention can be formulated as ointments, creams or lotions, or as transdermal patches. The ointments and creams can, for example, be formulated with an aqueous or oily base with the addition of appropriate thickening and / or gelling agents. Lotions can be formulated with an aqueous or oily base and in general they will also contain one or more emulsifying agents, stabilizing agents, dispersion, suspending agents, thickening agents, or coloring agents.

Compositions suitable for topical administration in the mouth include dragees comprising the active agent in a flavored base, generally sucrose and acacia or tragacanth; pills comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and rinses comprising the active ingredient in an appropriate liquid carrier.

The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, a pipette or aerosol. The compositions can be provided in single or multiple doses.

Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized package with an appropriate propellant such as chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide , or another appropriate gas. The aerosol may also conveniently contain a surfactant such as lein. The dose of drug can be controlled by the provision of a metering valve.

Alternatively, the active ingredients may be provided in the form of dry powder, for example a mixing powder of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition can be presented in the form of unit doses for example in capsules or cartridges of, for example, gelatin, or blister packs of which the powder can be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example in the order of 5 microns or less. Such a particle size can be obtained by means known in the prior art, for example by micronization.

When desired, compositions adapted to give sustained release of the active ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package contains discrete quantities of preparation, such as packed tablets, capsules, and powders in bottles or blisters Also, the unit dosage form can be a capsule, a tablet, a stamp, or a dragee by itself, or it can be the appropriate number of any of these in packaged form.

Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.

Additional details on the techniques for formulation and administration can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

A therapeutically effective dose refers to that amount of active ingredient, which improves the symptoms or condition. The therapeutic efficacy and toxicity, for example ED50 and LD50, can be determined by standard pharmacological procedures in cell cultures or experimental animals. The proportion of the dose between the therapeutic and toxic effects is the therapeutic index and can be expressed by the ratio LD5o / ED5o. Pharmaceutical compositions exhibiting large therapeutic indices are preferred.

The dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the desired result, and the Exact dosage must of course be determined by the doctor.

The actual dosage depends on the nature and severity of the disease being treated, and is within the discretion of the physician, and can be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect. However, it is currently contemplated that the pharmaceutical compositions contain from about 0.1 to about 500 mg of the active ingredient per individual doses, preferably from about 1 to about 100 mg, most preferably from about 1 to about 10 mg, are suitable for therapeutic treatments. .

The active ingredient can be administered in one or several doses per day. A result can satisfactorily, in certain cases, be obtained in a dose as low as 0.1 ug / kg i.v. 1 g / kg p.o. The upper limit of the dosage range is currently considered to be approximately 10 mg / kg i.v. and 100 mg / kg p.o. Preferred ranges are from about 0.1 g / kg / day i.v., and from about 1 g / kg to 100 mg / kg / day p.o.

Therapy Methods The indolyl-oxadiazolyl-diazabicyclononane derivatives of the present invention are modulators of the valuable monoamine and nicotinic, and therefore useful for the treatment of a range of foods that involve cholinergic dysfunction as well as a range of disorders responsive to the action of nAChR modulators.

In another aspect the invention provides a method for the treatment, prevention or alleviation of a disease or disorder or condition of a living animal body, including a human, whose disease, disorder or condition is sensitive to the modulation of cholinergic receptors and / or monoamine receptors, and the method comprises administering to a living animal body, including a human, in need thereof an effective amount of a compound of the invention.

In a preferred embodiment, the disease, disorder or condition is related to the central nervous system.

The preferred medical indications contemplated according to the invention are those indicated above.

It is currently contemplated that the appropriate dosing intervals are from 0.1 to 1000 milligrams daily, preferably 10-500 milligrams daily, and more preferred 30-100 milligrams daily, depending as is usual on the exact mode of administration, manner in which they are administered, the indication to which the administration is directed, the subject involved, the body weight of the subject involved, and in addition to the preference and experience of the responsible physician or veterinarian.

Eg emplos The invention is further illustrated with reference to the following examples, which are not intended to limit the scope of the invention in any way as claimed.

Example 1 Preparatory Example All reactions involving reagents or air-sensitive intermediates were developed under nitrogen and in anhydrous solvents. Magnesium sulfate was used as a drying agent in the analysis procedures and the solvents were evaporated under reduced pressure. 1, 4-Diazabicyclo [3.2.2] nonane (intermediate compound) The title compound was prepared according to J.

Med. Chem. 1993 36 2311-2320 (according to the slightly modified method described below). 1, 4-Diazabicyclo [3.2.2] nonane (intermediate compound) To the solution of 1,4-diazabicyclo [3.2.2] nonan-3-one (15.8 g, 113 mmol) in absolute dioxane (130 mL) LiAlH4 (4.9 g, 130 mmol) was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperature. Water was added dropwise to the reaction mixture (5 ml in 10 ml of dioxane), the mixture was stirred for 0.5 hour and then filtered through a glass filter. The solvent it was evaporated and the residue was distilled using the Kugelrohr apparatus at 90 ° C (0.1 mbar) to produce 1,4-diazabicyclo [3.2.2] nonane (11.1 g, 78%) as a colorless hygroscopic material. 1,4-Diazabicyclo [3.2.2] nonan-3 -one (intermediate compound) To the solution of 3-quinuclidinone hydrochloride (45 g, 278 mmol) in 90 ml of water were added hydroxylamine hydrochloride (21 g, 302 mmol) and sodium acetate (CH3COONax3H20, 83 g, 610 mmol), the mixture was stirred at 70 ° C for 1 hour and then cooled to 0 ° C. The separated crystalline material was filtered (without washing) and dried in vacuum to yield 40.0 g of oxime.

The 3-quinuclidinone oxime (40.0 g) was added for 2 hours in small portions to polyphosphoric acid preheated to 120 ° C (190 g). The temperature of the solution during the reaction was maintained at 130 ° C. After the addition of the whole oxime the solution was stirred for 20 minutes at the same temperature, and allowed to reach room temperature. The acid mixture was neutralized by a solution of potassium carbonate (500 g in 300 ml of water), transferred into a 2000 ml flask, diluted with 300 ml of water and extracted with chloroform (3 x 600 ml). The combined organic extracts were dried with sodium sulfate, the solvent was evaporated and the solid residue dried in vacuo to yield 30.0 g (77%) of the lactam mixture.

Crystallization of the mixture obtained from 1,4-dioxane (220 ml) gave 15.8 g (40.5%) of 1,4-diazabicyclo [3.2.2] nonan-3-one as large colorless crystals with m.p. of 211 212 ° C.

Method A Fumaric acid salt 4- [5- (l-Methyl-lH-indol-6-yl) - [1,3,4] oxadiazol-2-yl] -1,4-diaza-bicyclo [3.2.2] nonane (composite Al) A mixture of 5 - (1-met i 1 - 1 H - indol - 6 - i 1) - [1, 3, 4] oxadiazole -2 - 1 iol (1.25 g, 5.41 ramol), 1,4-Diazabicyclo [3.2 .2] nonane (0.69 g, 5.41 mmol) and 1-propanol (5 ml) was stirred at 130 ° C for 15 hours. The reaction mixture was allowed to cool to room temperature. Aqueous sodium hydroxide (1M) was added and the mixture was extracted twice with chloroform. The mixture was extracted twice with aqueous hydrochloric acid. The aqueous phase was washed with chloroform and made alkaline by adding sodium hydroxide (4M), followed by extraction three times with chloroform. The free base was isolated as a brown oil. Yield 500 mg (29%). The corresponding salt was obtained by the addition of a mixture of diethyl ether and methanol (9: 1) saturated with fumaric acid. Yield 250 mg (36%). LC-ESI-HRMS of [M + H] + shows 324.1823 Da. Cale. 324.182435 Da, dev. - O .4 ppm.

Fumaric acid salt 4- [5- [1- (2-fluoro-ethyl) -1H-indol-6-yl] - [1,3,4] oxadiazol-2-yl] -1,4-diaza-bicyclo [3.2.2] nonano (compound A2) It was prepared according to method A. 2- (1, 4-diazabicyclo [3.2.2] nonan-4-yl) -5- (lH-indol-6-yl) -1, 3, 4-oxadiazole free base (compound A3) It was prepared according to method A. LC-ESI-HRMS of [M + H] + shows 310.166 Da. Cale. 310.16624 Da, dev. -0.8 ppm. 2- (1, 4-diazabicyclo [3.2.2] nonan-4-yl) -5- (1-isopropylindol-6-yl) -1,3,4-oxadiazole free base (compound A4) It was prepared according to method A. LC-ESI-HRMS of [M + H] + sample 352.21219 Da. Cale. 352.21319 Da, dev. -2.8 ppm.

Fumaric acid salt 2 - (1,4-diazabicyclo [3.2.2] nonan-4-yl) -5- (1-ethylindol-6-yl) -1,4,4-oxadiazole (compound A5) It was prepared according to method A. LC-ESI-HRMS of [M + H] + sample 338.19734 Da. Cale. 338.19754 Da, dev. -0.6 ppm.

Method B 5- (l-Methyl-lH-indol-6-yl) - [1,3,4] oxadiazole-2-thiol (intermediate compound) A mixture of l-methyl-lH-indol-6-hydrazide carboxylic acid (2.8 g, 14.8 mmol), potassium hydroxide (0.91 g, 16.3 mmol) and methanol (50 mL) was stirred at room temperature for 30 min. Carbon disulfide (2.25 g, 29.6 mmol) was added and the mixture was stirred for 15 hours at reflux. The mixture was allowed to cool to room temperature, water was added, the pH was adjusted to 3 by adding concentrated aqueous hydrochloric acid. The crystalline product was isolated by filtration and washed with water. Yield 2.75 g (80%). 5- [1- (2-Fluoro-ethyl) -lH-indol-6-yl] - [1, 3, 4] oxadiazole-2-thiol (intermediate compound) It was prepared according to method B. 5- (lH-indol-6-yl) -1,3,4-oxadiazole-2-thiol (intermediate compound) It was prepared according to method B. 5- (1-lsopropylindol-6-yl) -1,3,4-oxadiazole-2-thiol (intermediate compound) It was prepared according to method B. 5- (1-Ethylindol-6-yl) -1,3,4-oxadiazole-2-thiol (intermediate compound) It was prepared according to method B.

Method C L-methyl-lH-indole-6-carboxylic acid hydrazide (intermediate compound) A mixture of methyl ester of 1-methyl-lH- Indole-6-carboxylic acid (3.2 g, 16.1 mmol), hydrazine monohydrate (8.5 g, 169 mmol) and methanol (50 mL) was stirred under reflux for 15 hours. The mixture was evaporated, water was added and the product was isolated by extraction with chloroform, followed by evaporation. 1 - (2-Fluoro-i1) -1H-indol-6-carboxylic acid hydrazide (intermediate compound) It was prepared according to method C. 1 - . 1 - . 1 - Et i 1 indole - 6 - carbohydraz ida (intermediate compound) It was prepared according to method C. 1 - I sopro i 1 indole - 6 - carbohydrazide (intermediate compound) It was prepared according to method C. 1H- indol-6-carbohydraz ida (intermediate compound) It was prepared according to method C.

Method D Methyl ester of 1-methyl-1-indol-6-carboxylic acid (intermediate compound) A mixture of methyl-6-indole carboxylate (3.0 g, 16.6 mmol), sodium hydride (1.0 g, 24.9 mmol), DMF (20 mL) was stirred for 1 hour at room temperature followed by the addition of iodomethane (4.7 g, 33.2 mmol) and stirring at room temperature for 15 hours. The mixture was extracted with chloroform and evaporated. The product was isolated by evaporation. performance 3. 2 g (100%).

Methyl ester of 1- (2-Fluoro-ethyl) -lH-indole-6-carboxylic acid (intermediate compound) It was prepared according to method D at 60 ° C and 1-fluoro-2-iodoethane.

Methyl-indole-6-carboxylate (commercially available) 1 - . 1 - 1-propro-1-indole-6-carboxylic acid methyl ester (intermediate compound) It was prepared according to method D at 60 ° C of 2-bromopropane. l-Ethylindol-6-carboxylic acid methyl ester (intermediate compound) It was prepared according to the method D of ethyl iodide Example 2 In vitro inhibition of 3H-ct-Bungarotoxin binding in rat brain In this example the affinity of a benzodioxolyl-oxadiazolyl-diazabicyclononane derivative of the invention for binding to an a7 subtype of nicotinic receptors is determined in a standard analysis performed essentially as described in for example WO 2006/087306.

The value of the test is presented as an IC50 (the concentration of the test substance that inhibits the specific binding of 3 H-to-bungarotoxin by 50%).

The result of this experiment is presented in the table 1 abaj o.

Table 1 Inhibition of 3H- -Bungarotoxin binding It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (9)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. An indolyl-oxadiazolyl-diazabicyclononane derivative represented by Formula I a stereoisomer thereof or a mixture of its stereoisomers, in marked or unlabelled form, or a pharmaceutically acceptable salt thereof, characterized in that Ar 'represents an indolyl group selected from 1H-indol-4-yl, lH-indol-5-yl, 1H-indol-6-yl and lH-indol-7-yl, whose indolyl group is optionally N-substituted with alkyl, alkenyl, alkynyl, haloalkyl or cycloalkyl; I C-substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, and amino.

2. The indolyl-oxadiazolyl-diazabicyclononane derivative according to claim 1, a stereoisomer thereof or a mixture of its stereoisomers, in labeled or unlabeled form, or a pharmaceutically acceptable salt thereof, characterized in that Ar 'represents an indolyl group selected from lH-indol-4-yl, lH-indol-5-yl, lH-indol-6-yl and lH-indol-7-yl, whose indolyl group is optionally N-substituted with alkyl, alkenyl, alkynyl, haloalkyl or cycloalkyl.

3. The indolyl-oxadiazolyl-diazabicyclononane derivative according to claim 1, characterized in that it is 4- [5- (1-Methyl-1H-indol-6-yl) - [1, 3, 4] oxadiazol-2-yl] -1,4-diaza-bicyclo [3.2.2] nonane; 4-. { 5- [1- (2-Fluoro-ethyl) -lH-indol-6-yl] - [1, 3, 4] oxadiazol-2-yl} -1,4-diaza-bicyclo [3.2.2] nonane; 2- (1, 4-diazabicyclo [3.2.2] nonan-4-yl) -5- (lH-indol-6-yl) -1,3,4-oxadiazole; 2- (1, 4-diazabicyclo [3.2.2] nonan-4-yl) -5- (1-isopropylindol-6-yl) -1, 3, 4-oxadiazole; or 2- (1, 4-diazabicyclo [3.2.2] nonan-4-yl) -5- (l-ethylindol-6-yl) -1,3,4-oxadiazole; a stereoisomer thereof or a mixture of its stereoisomers, in marked or unlabelled form, or a pharmaceutically acceptable salt thereof.

4. The indolyl-oxadiazolyl-diazabicyclononane derivative according to claim 1, characterized in that it is 4-. { 5- [1- (2- [18F] -Fluoro-ethyl) -lH-indol-6-yl] - [1,3,4] oxadiazol-2-yl} -l, 4-diaza-bicyclo [3.2.2] nonane; a stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition characterized in that it comprises a therapeutically effective amount of an indolyl-oxadiazolyl-diazabicyclononane derivative according to any of claims 1-4, a stereoisomer thereof or a mixture of its stereoisomers, in labeled or unlabeled form, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier or diluent.

6. The indolyl-oxadiazolyl-diazabicyclononane derivative according to any of claims 1-4, a stereoisomer thereof or a mixture of its stereoisomers, in labeled or unlabeled form, or a pharmaceutically acceptable addition salt thereof, characterized in that they are for use as a medicine.

7. The use of the indolyl-oxadiazolyl-diazabicyclononane derivative according to any of claims 1-4, a stereoisomer thereof or a mixture of its stereoisomers, in labeled or unlabeled form, or a pharmaceutically acceptable addition salt thereof, for the manufacture of a pharmaceutical composition / medicament for the treatment, prevention or alleviation of a mammalian disease, disorder or condition, including a human being, whose disease, disorder or condition is responsive to the modulation of cholinergic receptors and / or monoamine receptors.

8. The use according to claim 7, wherein the disease, disorder or condition is a cognitive disorder, learning deficit, deficit and memory dysfunction, Down syndrome, Alzheimer's disease, attention deficit, attention deficit with hyperactivity disorder (ADHD), Tourette syndrome, psychosis, depression, bipolar disorder, mania, manic depression, schizophrenia, deficits cognitive or attention-related schizophrenia, obsessive-compulsive disorders (OCD), panic disorders, eating disorders such as anorexia nervosa, bulimia and obesity, narcolepsy, nociception, AIDS dementia, senile dementia, autism, Parkinson's disease, Huntington, amyotrophic lateral sclerosis, anxiety, anxiety disorders without OCD, seizure disorders, epilepsy, neurodegenerative disorders, transient anoxia, induced neurodegeneration, neuropathy, diabetic neuropathy, peripheral dyslexia, tardive dyskinesia, hyperkinesis, mild pain, moderate or severe pain, Acute, chronic or recurrent pain, pain caused by mig raña, postoperative pain, phantom limb pain, inflammatory pain, neuropathic pain, chronic headache, central pain, pain related to diabetic neuropathy, postherpetic neuralgia, or peripheral nerve injury, bulimia, post-traumatic syndrome, social phobia, sleep disorders, pseudodementia, Ganser syndrome, pre-menstrual syndrome, late luteal phase syndrome, fibromyalgia, chronic fatigue, mutism, trichotillomania, hourly decompensation, arrhythmias, smooth muscle contractions, angina pectoris, premature labor, diarrhea, asthma, tardive dyskinesia, hyperkinesia, premature ejaculation, erectile difficulty, hypertension, inflammatory disorders, inflammatory skin disorders, acne, rosacea, Crohn's disease, inflammatory bowel disease, ulcerative colitis, diarrhea, or withdrawal symptoms caused by termination of use of addictive substances, including nicotine-containing products such as tobacco, opioids such as heroin, cocaine, and morphine, benzodiazepines and drugs similar to benzodiazepine, and alcohol.

9. A pharmaceutical composition characterized in that it comprises a diagnostically effective amount of an indolyl-oxadiazolyl-diazabicyclononane derivative labeled according to any of claims 1-4, a stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier or diluent.